This application directs a career and research development plan for Dr. Alicia Mathers, an immunology trained post-doctoral fellow committed to a research program in cutaneous immunology and the understanding of the dendritic cell (DC) mechanism(s) involved in the induction of skin inflammation and adaptive immunity. This proposal will assist Dr. Mathers in her current goal of transitioning to an independent investigator and her long-term goal of being a leader in the field of cutaneous immunology. To obtain her short-term goal of transitioning Dr. Mathers will complete current research projects with Dr. Larregina and submit the data for publication while also obtaining training from career development courses. Dr. Mathers has a strong background in Immunology with a focus on DC biology thus the career plan detailed in this proposal enhances her Immunology base while also providing further training in the field of Dermatology so that she will be competitive in research focused on cutaneous immunology. Her career plan is enhanced by her research plan to explore cutaneous immune responses initiated by DCs. Prior investigations by Dr. Mathers utilizing an ex vivo model of human epidermal-dermal explants has demonstrated that skin migratory DCs (smiDCs) induce the co-existence of CD4+ T helper (Th) 17 and Th1 responses. Furthermore, she has demonstrated that epidermal resident Langerhans cells (LCs), and not dermal DCs (DDCs), are the cutaneous DC subset responsible for initiating Th17 immunity. Therefore the hypothesis of this proposal is that "Differences observed in the Th17-biasing capacity of cutaneous DC populations is conferred through the differential release of innate endogenous danger-signals by their respective microenvironments". Thus, the goal of this proposal is to examine the possibility that the epidermal danger signals known as alarmins, including the high mobility group box 1 (HMGB1) and ATP, are responsible for the Th17-biasing functions of both human and murine LCs, and whether DDCs exposed to similar Th17-biasing conditions as LCs will gain the capacity to initiate and sustain Th17 immunity. To test our hypothesis we propose the following specific aims: Specific aim 1 will examine the abilities of the epidermal endogenous alarmins HMGB1 and ATP to activate human LCs capable of initiating Th17 responses, co-existent with Th1 cells. Specific aim 2 will determine if human DDCs have the capacity to initiate Th17 responses when treated with Th17-biasing stimuli. Specific aim 3 will analyze the ability of murine cutaneous DCs to induce Th17 responses. Relevance: Th17 responses are necessary for the induction of efficient immune responses to infectious diseases. Conversely, Th17 cells are implicated in the development and relapse of cutaneous inflammatory and autoimmune pathologies. Therefore, a better understanding of how Th17 immunity is initiated and sustained will have a positive impact on rational vaccine design and for the development of new therapeutic targets for cutaneous autoimmune diseases.